ALSUntangled #73: Lion's Mane.

Lion's Mane (Hericium erinaceus) has historically been used as traditional medicine in Asia and Europe for its potential benefits in fighting infection and cancer. It has gained interest in the neurodegenerative disease field because of its mechanisms of action; these include anti-inflammation, neuroprotection, and promoting neurite growth demonstrated in various cell and animal models. A very small, double-blind, placebo-controlled trial in patients with mild cognitive impairment showed a temporary improvement in cognitive function; this finding has yet to be replicated. However, there have been no studies in ALS cell or animal models or in humans with ALS. Lion's Mane appears safe and inexpensive when consumed in powder or capsule, but one anaphylactic case was reported after a patient consumed fresh Lion's Mane mushroom. Currently, we do not have enough information to support the use of Lion's Mane for treating ALS. We support further research in ALS disease models and clinical trials to study its efficacy.

ALSUntangled #70: caffeine.

ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here, we review caffeine which has plausible mechanisms for slowing ALS progression. However, pre-clinical studies are contradictory, and a large case series showed no relationship between caffeine intake and ALS progression rate. While low doses of caffeine are safe and inexpensive, higher doses can cause serious side effects. At this time, we cannot endorse caffeine as a treatment to slow ALS progression.

Dr. Aníbal Zambrano: un médico peruano con corazón de oro / Aníbal Zambrano, M.D: a Peruvian physician with a heart of gold

RESUMEN El objetivo del artículo es describir y analizar la trayectoria de vida y las contribuciones humanitarias del Dr. Zambrano, médico egresado de la Escuela de Medicina de San Fernando, quién fue presidente del Centro de Estudiantes de Medicina en una época políticamente álgida en la educación universitaria pública. Emigró a los Estados Unidos en 1970, bajo el contexto de crisis sociopolítica económica en el Perú y en el mundo, donde se convirtió en un renombrado médico internista y cardiólogo del St. Luke's Hospital. A pesar de su lejanía, mantuvo un lazo estrecho con el Perú organizando múltiples misiones médicas para el beneficio de poblaciones vulnerables, capacitación al personal médico e implementación tecnológica del Hospital Regional de Cajamarca. En 2011 se inauguró el Centro Médico Educativo en Chincha, siendo Zambrano uno de los líderes para su construcción. A pesar de padecer una enfermedad invalidante dedicó hasta los últimos días de su vida a brindar ayuda a los más necesitados. Su trayectoria de vida nos muestra un ejemplo de compromiso con el Perú y de un ejercicio de la medicina comprometida con la solidaridad y el desarrollo de la medicina en su país de origen.

ABSTRACT The objective of the article is to describe and analyze the life trajectory and the humanitarian contributions of Dr. Zambrano, a physician who graduated from San Fernando Medical school, and was president of the Center for Medical Students at a politically critical time in public university education. He emigrated to the United States in 1970, in the context of sociopolitical crisis in Peru and the world, where he became a renowned internist and cardiologist at St. Luke's Hospital. Despite the distance, he maintained a close relationship with Peru, organizing multiple medical missions for underserved populations, training medical personnel, and providing technological implementation to Cajamarca Regional Hospital. In 2011, the Educational Medical Center was inaugurated in Chincha, with Zambrano being one of the leaders for its construction. Despite suffering from a disabling illness, he dedicated until the last days of his life, providing help for those most in need. His life trajectory shows us an example of commitment to Peru and practice of Medicine committed to solidarity and the development of Medicine in his country of origin.

Case Study of an Elderly Patient With New Onset Weakness.

ABSTRACT: We present a patient presented with new onset progressive proximal weakness. On examination noted to have proximal weakness on upper and lower limbs, with preserved reflexes, without sensory involvement. Blood work revealed to have elevated creatine kinase. On electromyography testing shows myopathic features and also noted to have myotonic discharges. Muscle biopsy was obtained next which showed many vacuolization, marked increase in all fat content noted. These findings led us to checking carnitine levels which were noted to be significantly reduced with elevated carnitine palmitoyltransferase levels. These findings highly suggestive of systemic carnitine deficiency. Secondary causes of systemic Carnitine deficiency not identified in this patient and presumed to have primary systemic carnitine deficiency. Patient improved on oral supplementation of L- Carnitine.

Clinical Effects of the Self-administered Subcutaneous Complement Inhibitor Zilucoplan in Patients With Moderate to Severe Generalized Myasthenia Gravis: Results of a Phase 2 Randomized, Double-Blind, Placebo-Controlled, Multicenter Clinical Trial.

Importance: Many patients with generalized myasthenia gravis (gMG) have substantial clinical disability, persistent disease burden, and adverse effects attributable to chronic immunosuppression. Therefore, there is a significant need for targeted, well-tolerated therapies with the potential to improve disease control and enhance quality of life. Objective: To evaluate the clinical effects of zilucoplan, a subcutaneously (SC) self-administered macrocyclic peptide inhibitor of complement component 5, in a broad population of patients with moderate to severe gMG. Design, Setting, and Participants: This randomized, double-blind, placebo-controlled phase 2 clinical trial at 25 study sites across North America recruited participants between December 2017 and August 2018. Fifty-seven patients were screened, of whom 12 did not meet inclusion criteria and 1 was lost to follow-up after randomization but before receiving study drug, resulting in a total of 44 acetylcholine receptor autoantibody (AChR-Ab)-positive patients with gMG with baseline Quantitative Myasthenia Gravis (QMG) scores of at least 12, regardless of treatment history. Interventions: Patients were randomized 1:1:1 to a daily SC self-injection of placebo, 0.1-mg/kg zilucoplan, or 0.3-mg/kg zilucoplan for 12 weeks. Main Outcomes and Measures: The primary and key secondary end points were the change from baseline to week 12 in QMG and MG Activities of Daily Living scores, respectively. Significance testing was prespecified at a 1-sided α of .10. Safety and tolerability were also assessed. Results: The study of 44 patients was well balanced across the 3 treatment arms with respect to key demographic and disease-specific variables. The mean age of patients across all 3 treatment groups ranged from 45.5 to 54.6 years and most patients were white (average proportions across 3 treatment groups: 78.6%-86.7%). Clinically meaningful and statistically significant improvements in primary and key secondary efficacy end points were observed. Zilucoplan at a dose of 0.3 mg/kg SC daily resulted in a mean reduction from baseline of 6.0 points in the QMG score (placebo-corrected change, -2.8; P = .05) and 3.4 points in the MG Activities of Daily Living score (placebo-corrected change, -2.3; P = .04). Clinically meaningful and statistically significant improvements were also observed in other secondary end points, the MG Composite and MG Quality-of-Life scores. Outcomes for the 0.1-mg/kg SC daily dose were also statistically significant but slower in onset and less pronounced than with the 0.3-mg/kg dose. Rescue therapy (intravenous immunoglobulin or plasma exchange) was required in 3 of 15, 1 of 15, and 0 of 14 participants in the placebo, 0.1-mg/kg zilucoplan, and 0.3-mg/kg zilucoplan arms, respectively. Zilucoplan was observed to have a favorable safety and tolerability profile. Conclusions and Relevance: Zilucoplan yielded rapid, meaningful, and sustained improvements over 12 weeks in a broad population of patients with moderate to severe AChR-Ab-positive gMG. Near-complete complement inhibition appeared superior to submaximal inhibition. The observed safety and tolerability profile of zilucoplan was favorable. Trial Registration: ClinicalTrials.gov Identifier: NCT03315130.

A Case of Triple-Negative Myasthenia Gravis Lambert-Eaton Overlap Syndrome With Negative Agrin and LRP-4 Antibodies.

A case of triple-negative myasthenia gravis Lambert-Eaton overlap syndrome with negative Agrin and LRP-4 antibodies. Myasthenia gravis (MG) is an autoimmune disorder that shares similar features with Lambert-Eaton myasthenic syndrome. The combined clinical and electrophysiological findings of MG and Lambert-Eaton myasthenic syndrome have been reported, these cases represent the so-called "myasthenia gravis Lambert-Eaton overlap syndrome" (MLOS). A total of 55 MLOS cases have been identified, 13 cases were reported before the acetylcholine receptor (AChR) antibody (ab) testing era, 14 during the AChR-ab era, 26 during the voltage-gated calcium channel (VGCC)-ab era, and 2 cases have been reported during the muscle-specific kinase (MuSK)-ab era, of these; only 1 patient tested negative for all 3 antibodies. New immunological markers have been identified in the study of MG [Agrin and the low-density lipopro-tein receptor-related protein 4 (LRP-4)]. We present a patient with MLOS who tested negative for all 5 (AChR, MuSK, VGCC, Agrin, and LRP-4) serologic markers.

Miopatías autoinmunes: revisión de diagnóstico y manejo / Autoimmune myopathies: diagnosis and management review

Las miopatías inflamatorias idiopáticas (MII) son un grupo de enfermedades autoinmunes crónicas que afectan principalmente a los músculos proximales. Los tipos más comunes son dermatomiositis (DM), polimiositis (PM), miopatía autoinmune necrotizante y miositis por cuerpos de inclusión. Se identifican de forma única por su presentación clínica que consiste en manifestaciones musculares y extramusculares, sus alteraciones miopáticas en el electromiograma y la elevación de las enzimas musculares. Sin embargo, la biopsia muscular sigue siendo el gold estándar para el diagnóstico. Estos trastornos son potencialmente tratables con un diagnóstico adecuado. Los objetivos del tratamiento son eliminar la inflamación, restaurar el rendimiento muscular, reducir la morbilidad y mejorar la calidad de vida. Esta revisión tiene como objetivo proporcionar un enfoque de diagnóstico básico a los pacientes con sospecha de MMI a través de sus principales hallazgos clínicos, de laboratorio e histopatológicos.

Idiopathic inflammatory myopathies (MII) are a group of autoimmune diseases that mainly affect the proximal muscles. The most common types are Dermatomyositis (DM), Polymyositis (PM), Necrotizing autoimmune myopathy and Inclusion body myositis. Unique forms are identified in their clinical presentation consisting of muscular and extramuscular manifestations, their myopathic alterations in the electromyogram and the elevation of muscle enzymes. However, muscle biopsy remains the gold standard for diagnosis. These disorders are tratable with a proper. The goals of treatment are to eliminate inflammation, restore muscle performance, reduce morbidity and improve quality of life.This review aims at a basic diagnostic approach in patients with suspicion of MMI through its main clinical, laboratory and histopathological findings.

ULK1 and ULK2 Regulate Stress Granule Disassembly Through Phosphorylation and Activation of VCP/p97.

Disturbances in autophagy and stress granule dynamics have been implicated as potential mechanisms underlying inclusion body myopathy (IBM) and related disorders. Yet the roles of core autophagy proteins in IBM and stress granule dynamics remain poorly characterized. Here, we demonstrate that disrupted expression of the core autophagy proteins ULK1 and ULK2 in mice causes a vacuolar myopathy with ubiquitin and TDP-43-positive inclusions; this myopathy is similar to that caused by VCP/p97 mutations, the most common cause of familial IBM. Mechanistically, we show that ULK1/2 localize to stress granules and phosphorylate VCP, thereby increasing VCP's activity and ability to disassemble stress granules. These data suggest that VCP dysregulation and defective stress granule disassembly contribute to IBM-like disease in Ulk1/2-deficient mice. In addition, stress granule disassembly is accelerated by an ULK1/2 agonist, suggesting ULK1/2 as targets for exploiting the higher-order regulation of stress granules for therapeutic intervention of IBM and related disorders.

A Case of Asymptomatic Inclusion Body Myositis.

OBJECTIVES: To present a case of asymptomatic inclusion body myositis. METHODS: The authors report a case of a 67-year-old man who presented with idiopathic hyperCKemia. Physical examination including a complete neurological evaluation was unremarkable. Systemic causes of hyperCKemia, including medication side effects, metabolic and endocrine disorders, and connective tissue disorders, were ruled out with various indicated tests. RESULTS: Two and a half years after initial consultation, the patient reported left knee pain. Magnetic resonance imaging of the left knee showed edema in the mid and distal aspect of the vastus medialis and vastus lateralis muscles. A biopsy of the left quadriceps muscles was diagnostic of inclusion body myositis. He remained asymptomatic for the ensuing 2.5 years. CONCLUSIONS: Asymptomatic hyperCKemia should be investigated and followed closely for definitive diagnosis and possible treatable causes.

Somatic mosaicism due to a reversion variant causing hemi-atrophy: a novel variant of dystrophinopathy.

We describe a case of hemi-atrophy in a young adult male, with a positive family history of three maternal uncles with Duchenne muscular dystrophy (DMD). The patient showed progressive weakness localized to the left side, an abnormal electromyography, and creatine kinase levels >3000 IU/l. Muscle biopsy showed both dystrophin-positive and -negative myofibers. An out-of-frame duplication variant in DMD, that is, c.(93+1_94-1)_(649+1_650-1)dup(p.?) resulting in duplication of exons 3-7 was inherited, but the muscle biopsy showed dystrophin mRNA with and without the duplication. Dystrophin quantification using mass spectrometry showed 25% normal dystrophin protein levels in the muscle biopsy from the stronger right side. Sex chromosome aneuploidy was ruled out. We conclude that the patient inherited the duplication variant, but early in development an inner cell mass underwent a somatic recombination event removing the duplication and restoring dystrophin expression. To our knowledge, this is the first report of a reversion leading to somatic mosaicism in DMD.

A multi-center screening trial of rasagiline in patients with amyotrophic lateral sclerosis: Possible mitochondrial biomarker target engagement.

Rasagiline, a monoamine oxidase B inhibitor, slowed disease progression in the SOD1 mouse, and in a case series of patients with amyotrophic lateral sclerosis (ALS). Here we determine whether rasagiline is safe and effective in ALS compared to historical placebo controls, and whether it alters mitochondrial biomarkers. We performed a prospective open-label, multicenter screening trial of 36 ALS patients treated with 2 mg oral rasagiline daily for 12 months. Outcomes included the slope of deterioration of the revised ALS Functional Rating Scale (ALSFRS-R), adverse event monitoring, time to treatment failure, and exploratory biomarkers. Participants experienced no serious drug-related adverse events, and the most common adverse event was nausea (11.1%). Rasagiline did not improve the rate of decline in the ALSFRS-R; however, differences in symptom duration compared to historical placebo controls differentially affected ALSFRS-R slope estimates. Rasagiline changed biomarkers over 12 months, such that the mitochondrial membrane potential increased (JC-1 red/green fluorescent ratio 1.92, p = 0.0001) and apoptosis markers decreased (Bcl-2/Bax ratio 0.24, p < 0.0001). In conclusion, engagement of exploratory biomarkers and questions about comparability of baseline characteristics lead us to recommend a further placebo-controlled trial.

An adult male with progressive spastic paraparesis and gait instability.

This is a case of an adult male with history of motor difficulties, speech, and behavioral problems since early childhood found to have progressive spastic paraparesis, impaired vibration and proprioception, and gait instability. His medical history included bilateral cataracts status post surgical removal at the age of 30, cholelithiasis status post cholecystectomy at age 45, and high cholesterol levels.

Neurologic complications of disorders of the adrenal glands.

Disorders of the adrenal glands frequently have secondary neurological manifestations, while some diseases that involve the central nervous system are accompanied by adrenal gland dysfunction. Excessive corticosteroid secretions in primary or secondary Cushing's syndrome causes muscle weakness and behavioral disturbances, such as emotional lability and sometimes depression, while adrenal insufficiency may cause fatigue, weakness, and depression. Adrenoleukodystrophy and adrenoneuromyelopathy are X-linked recessive disorders of the metabolism of very long chain fatty acids that manifest with white matter abnormalities of the brain, myelopathy and/or neuropathy, as well as adrenal insufficiency. Other disorders of the adrenal glands include hyperaldosteroidism, which may cause weakness from hypokalemia. Dysfunction of the adrenal medulla causes excessive or deficient secretion of catecholamines, primarily causing cardiovascular symptoms. This chapter reviews the clinical manifestations and diagnostic aspects and treatment of the various disorders of the adrenal glands. Some of the congenital adrenal diseases are also discussed.

Dermatomyositis presenting with focal scleroderma-like skin changes.

OBJECTIVE: To describe an unusual focal scleroderma-like skin changes in patient with dermatomyositis. METHODS: Review of clinical records, laboratory investigations, and muscle and skin biopsies. RESULTS: The patient developed unusual skin lesions characterized by symmetrical atrophy and hardening of focal skin and muscle over the lateral upper arms and posterior shoulders, and the left temporal and pectoral areas. Extensive blood work-up for scleroderma and other connective-tissue diseases was negative. A skin biopsy showed distinct pathologic features including increased interstitial mucin, hyperpigmentation, and perivascular lymphocytic inflammation without severe fibrosis. The scleroderma-like skin changes and muscle weakness improved with immunotherapy. CONCLUSIONS: Dermatomyositis can manifest with focal scleroderma-like skin changes clinically and reticular erythematous mucinosis-like changes pathologically, and these distinct skin changes represent a new variant of skin lesions of dermatomyositis.

A fatal presentation of dermatomyositis with facial swelling.

Juvenile dermatomyositis (JDM) is the most common inflammatory autoimmune myopathy in children. Most common presentations consist of heliotrophic rash and/or gottron's papules in addition to proximal muscle weakness. A typical presentations have been reported. We present a 13-year-old African American male who presented with a two-week history of bilateral periorbital edema that was unresponsive to glucocorticoids. He had elevated transaminases but no detectable muscle weakness. A muscle biopsy was consistent with juvenile dermatomyositis. This case highlights the need to consider dermatomyositis in cases of facial swelling and the use of aggressive immunosuppressive therapies due to its associated vasculopathies.

Limb edema and anasarca associated with severe dermatomyositis: report of four cases.

Dermatomyositis is an autoimmune disorder that causes proximal muscle weakness and skin changes which include generalized erythema, heliotrope rash and/or Gottron's papules. Generalized or limb edema is an uncommon manifestation of dermatomyositis. Here, we report four cases who presented with generalized or limb edema, proximal muscle weakness, erythematous skin rash and/or dysphagia. Muscle biopsy revealed perifascicular fiber atrophy, a characteristic finding of dermatomyositis. The absence of other causes indicated that the generalized or limb edema was caused by dermatomyositis. None of our patients showed significant improvement with steroids alone, and more aggressive immunotherapy eventually resolved the edema. We concluded that generalized or limb edema may be a hallmark of a severe form of dermatomyositis and requires prompt and aggressive therapies.

A female with progressive four-limb paresthesias and gait difficulty.

EDUCATIONAL OBJECTIVES: To discuss a case of progressive four-limb paresthesias and gait difficulty in a female who had previously undergone gastric bypass surgery. KEY QUESTIONS: 1) What is the differential diagnosis of progressive four-limb paresthesias and gait difficulty? 2) How would one approach diagnostic testing for such a patient? 3) What are the complications of gastric bypass surgery? 4) What is the treatment for this patient?

Clinical findings in MuSK-antibody positive myasthenia gravis: a U.S. experience.

We performed a retrospective chart review on 53 muscle-specific kinase antibody (MuSK-Ab)-positive myasthenia gravis (MG) patients at nine university-based centers in the U.S. Of these, 66% were Caucasian, 85% were women, and age of onset was 9-79 years. Twenty-seven patients were nonresponsive to anticholinesterase therapy. Myasthenia Gravis Foundation of America improvement status was achieved in 53% patients on corticosteroids, 51% with plasma exchange, and in 20% on intravenous immunoglobulin (IVIG). Thymectomy was beneficial in 7/18 patients at 3 years. Long-term (> or =3 years) outcome was very favorable in 58% of patients who achieved remission and/or minimal manifestation status. Overall, 73% improved. There was one MG-related death. This survey reinforces several cardinal features of MuSK-Ab-positive MG, including prominent bulbar involvement and anticholinesterase nonresponsiveness. Facial or tongue atrophy was rare. Most patients respond favorably to immunotherapy. The best clinical response was to corticosteroids and plasma exchange, and the poorest response was to IVIG. Long-term outcome is favorable in about 60% of cases.

Transient neonatal myasthenia gravis in a baby born to a mother with new-onset anti-MuSK-mediated myasthenia gravis.

We describe a 30-year-old pregnant woman with undiagnosed weakness who delivered a severely weak neonate. Subsequent workup of the mother revealed myasthenia gravis with muscle-specific kinase antibodies. The infant responded to intravenous immunoglobulin and symptoms normalized. He was presumed to have an anti-muscle-specific kinase-mediated transient neonatal myasthenia gravis.

Leucoencephalopathy, transverse myelopathy, and peripheral neuropathy in association with glutamic acid decarboxylase-65 (GAD) antibodies in children with cancer.

Neurologic toxicity may occur as a direct effect of cancer and its therapy or indirectly because of a dysfunctional immune system. The authors report the development of axonal neuropathy, myelopathy, and leucoencephalopathy associated with glutamic acid decarboxylase-65 (GAD) antibodies in 4 children with progressive cancer who were heavily pretreated. Three patients with refractory leukemia and 1 with Ewing sarcoma developed paraplegia with sensory level and dorsal column dysfunction. Three developed leucoencephalopathy and 1 died of neurologic disease. All had high serum titers of GAD antibodies during the progressive phase of the illness, and the antibody levels returned to normal with the stability of the neurologic disease. Three survivors are showing gradual recovery. This syndrome of central and peripheral nervous system toxicity may have resulted from chemotherapy toxicity or from immune dysfunction, as suggested by the high GAD antibody titers.